Mild method for the synthesis of 1H-indazoles through oxime-phosphonium ion intermediate

Article abstract of DOI:10.1016/j.tetlet.2014.03.001

The synthesis of 1H-indazoles from o-aminobenzoximes is achieved via N-N bond formation using triphenylphosphine, I₂, and imidazole. Selective formation of oxime-phosphonium ion intermediate in the presence of the amino group is the driving for

Full text of DOI:10.1016/j.tetlet.2014.03.001

Tetrahedron Letters 55 (2014) 2480–2483
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mild method for the synthesis of 1H-indazoles
through oxime-phosphonium ion intermediate
⇑
Saurav Paul, Subhankar Panda, Debasis Manna
Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 1H-indazoles from o-aminobenzoximes is achieved via N–N bond formation using
triphenylphosphine, I2, and imidazole. Selective formation of oxime-phosphonium ion intermediate in
the presence of the amino group is the driving force for this reaction. The nucleophilicity of the arylamino
group and electrophilicity toward the N–O bond of oxime also control the reaction. The reaction proceeds
at a faster rate with good to excellent yield under this mild reaction condition and is amenable to
scale-up.
Received 5 February 2014
Revised 1 March 2014
Accepted 2 March 2014
Available online 11 March 2014
Keywords:
1H-Indazoles
Ó 2014 Elsevier Ltd. All rights reserved.
Oxime-phosphonium ion intermediate
N–N bond formation
Mild reaction condition
Basic medium
Pharmacologically active 1H-indazole and its derivatives are
widely used as drug in treating various human diseases including
cancer, inflammation, cardiovascular, and others.1–3 This has in-
cited researchers in developing innovative methods toward their
synthesis. The synthesis of substituted 1H-indazole has been al-
ready accomplished by various chemical methods, but only a few
methods offer mild, transition-metal-free reaction condition.4–9
Most of the reported transition-metal-free reaction methods such
as diazotization or nitrosation of o-alkyl substituted anilines,
condensation of hydrazine with o-halo- or mesylate-containing
aldehydes or ketones, and cycloaddition of diazomethanes with
benzynes require stringent or inconvenient conditions.4–7 There
have been ongoing efforts in recent years aimed at developing
mild, transition-metal-free reaction protocols for the synthesis of
substituted 1H-indazole with improved efficiency. Blom and
co-workers recently reported a mild, base-catalyzed method for
the synthesis of substituted indazoles through condensation of
o-halo- substituted ketones and tosylhydrazone.10 Among the
other reported metal-free reaction processes, a study by Stambuli
and co-workers to synthesize substituted indazoles via N–N bond
formation caught our attention.11 They reported that selective acti-
vation of the hydroxyl group of the oxime in the presence of the
arylamino group is the key step for the synthesis of 1H-indazole
under basic condition. Interestingly, Robles and co-workers, and
our group reported the esterification process using the similar con-
cept of selective activation of the alkyl or aryl acid group.12,13 We
hypothesized that selective activation of the hydroxyl group of
the oxime by using triphenylphosphine, I2, and base would pro-
duce a suitable leaving group in the presence of arylamine. The
presence of mild base would then trigger an intramolecular nucle-
ophilic attack by the arylamino group onto the activated oxime to
produce the desired 1H-indazole.
For the initial screening and optimization of the reaction condi-
tion, oxime of o-amino benzophenone was chosen as substrate. For
the N–N bond formation in the presence of Ph3P/I2, different bases
and solvents were tested, and the reaction parameters (tempera-
ture, time) were altered. The best result was obtained with imidaz-
ole (3.3 equiv) as a base and CH2Cl2 as solvent at room temperature
for 4 h (Table 1). However, lower amount of imidazole (<3.3 equiv)
reduced the amount of 1H-indazole derivatives. The use of other
bases including, tetrazole, Et3N, pyridine, DBU, DIPA, and DMAP re-
sulted poor or no yield, under the similar experimental condition.
The use of other solvents including DMF, THF, and CH3CN also
produced poor yield. There was no significant improvement in
the 1H-indazole formation for a longer time or even at a higher
temperature.
It is reported that oximes undergo Beckmann rearrangement to
produce amides or nitriles at ambient temperature.14 However, we
observed little or no Beckmann rearrangement product for the
examined substrates (Table 2) under the optimized reaction condi-
tions. This could be due to the basic reaction medium and stronger
nucleophilicity of the arylamino group over the rearrangement
⇑
Corresponding author. Tel.: +91 03 61258 2325; fax: +91 03 61258 2349.
E-mail address: dmanna@iitg.ernet.in (D. Manna).
process. It is also reported that oximes with a-proton can undergo
http://dx.doi.org/10.1016/j.tetlet.2014.03.001
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Paul et al. / Tetrahedron Letters 55 (2014) 2480–2483
2481
Table 1
Screening and optimization of the reaction conditions
Ph
Ph
N
OH
Ph3P (1.5 equiv), I2 (1.5 equiv),
base (3.5 equiv), solvent
N
N
NH2
1a
2a
H
Entry
Phosphine/I2
Base
Solvent
Temperature (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
Ph3P/I2
Ph3P/I2
Ph3P/I2
Ph3P/I2
Ph3P/I2
Ph3P/I2
Ph3P/I2
Ph3P/I2
Ph3P/I2
Imidazole
Et3N
Diisopropylamine
Tetrazole
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
CH3CN
THF
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
60
4
4
4
4
4
4
4
10
4
72
N.R
15
30
10
N.R
N.R
74
75
a
Isolated yields.
Table 2
Synthesis of 1H-indazoles from oximes
R1
R1
OH
N
Ph3P (1.5 equiv), I2 (1.5 equiv),
R
R
N
imidazole (3.5 equiv), CH2Cl2,
rt, 4 h
N
H
NH2
1
2
Entry
1
Oxime
Indazole
Yielda (%)
72
Ph
Ph
N
OH
N
N
1a
2a
NH2
H
Ph
Ph
N
H3CO
H3CO
F
OH
N
2
3
4
5
6
7
8
9
88
—
N
H
2b
1b
NH2
Ph
OH
NRb
N
1c
NH2
C6H4-m-Cl
C6H4-m-Cl
OH
N
78
80
75
85
87
48
N
N
H
2d
1d
NH2
C6H4-p-Cl
C6H4-p-Cl
OH
N
N
2e
N
H
1e
NH2
C6H4-p-Br
C6H4-p-Br
OH
N
N
N
H
2f
1f
NH2
C6H3-m-Cl-p-Cl
C6H3-m-Cl-p-Cl
OH
N
N
N
H
2g
1g
NH2
C6H3-m-Cl-p-Cl
C6H3-m-Cl-p-Cl
H3CO
H3CO
OH
N
N
N
H
2h
1h
NH2
CH3
N
CH3
OH
N
2i
N
H
1i
NH2
a
Isolated yields.
No reaction.
b

2482
S. Paul et al. / Tetrahedron Letters 55 (2014) 2480–2483
Table 3
I2
Ph
Ph
Ph
Ph
N
I
HN
Substrate scope of the optimized reaction conditions
P
P I
+
Ph
I
Ph
Entry
Oxime
Indazole
Yielda (%)
CH3
N
CH3
N
Ph
P
I
Ph
N
Ph
HI
OH
+
N
Ph
1
64
—
N
4a
CH3
N
N
II
Ph
N OH
NH2
N
H
H
CH3
3a
CH3
Ph
N O
NH2
Ph
P
OH
Ph
Ph P O
Ph
N
NRb
Ph
I
2
3
N
+
I
H2N
Ph
TS
3b
N
H
III
CH3
CH3
OH
OH
N
Scheme 1. Plausible mechanistic pathway for the synthesis of 1H-indazoles
through N–N bond formation.
N
48
N
4c
N
H
3c
Ph
Ph
H
N
analyzing the reactivity of benzophenone-oxime and substituted
anilines using these optimized reaction conditions. The benzophe-
none phenylhydrazones were obtained with moderate to good
yield. A similar effect of the electron-withdrawing group was also
observed for these compounds (Table 3).
N
N
4
5
68
54
3d
Ph
4d
Ph
H
N
OH
It is also important to note that, the intramolecular nucleophilic
substitution mechanism is only possible for the (E) isomer of the
activated oxime. Meanwhile, complete conversion of o-amino-
benzoximes to 1H-indazole clearly indicates the formation of only
(E) isomer of the activated oxime, under the experimental condi-
tions. This could be because of the formation of predominantly
(E) isomer of the oxime from the corresponding benzophenone.
Based on the experimental results and previous mechanistic
studies, we suggest the following mechanism (Scheme 1) for the
synthesis of 1H-indazoles. The reaction between Ph3P, I2, and imid-
azole yielded the intermediate (II), and subsequent attack of oxime
of o-amino benzophenone selectively generates the oxime-phos-
phonium ion intermediate (III). The intramolecular nucleophilic at-
tack by the arylamino group onto the Sp2-nitrogen center of the
activated oxime (III) generates the desired 1H-indazole under basic
media. This could be the rate-determining step for the synthesis of
1H-indazole through N–N bond formation. To obtain further
understanding of the reaction mechanism, we also performed the
reaction of oxime of benzophenone with aniline under the similar
experimental condition. The formation of these proposed interme-
diates in the reaction mixture was studied by 31P NMR spectros-
N
N
3e
4e
Cl
a
Isolated yields.
No reaction.
b
Neber rearrangement at this ambient temperature.15 We did not
observe any such rearrangement products for oximes with -pro-
a
ton under the optimized reaction conditions (Table 2, entry 9).
We hypothesized that mild basicity of the imidazole makes the
arylamino group sufficiently strong nucleophile for the formation
of N–N bond through oxime-phosphonium ion intermediate, with-
out any migration product under these optimized reaction condi-
tions. Therefore, the conversion of oximes to 1H-indazoles under
these optimized reaction conditions is facile and avoids the Beck-
mann and Neber rearrangement products.
Encouraged by this excellent result, we decided to determine the
scope of this methodology for the synthesis of several other substi-
tuted 1H-indazoles by analyzing the reactivity of various oximes of
o-amino benzophenone using the optimized reaction conditions
(Table 2). We also investigated the role of R and R1 groups in 1H-
indazole formation. The oximes with R as the electron-donating
group produced the desired indazoles with excellent yields (88–
87%). Whereas, oximes with R1 as the electron-withdrawing group
produced poor/no yield. The results clearly showed that the nucle-
ophilicity of the arylamino group has a direct effect on the N–N
bond formation under the optimized reaction conditions. Similarly,
oximes with R1 as the electron-withdrawing group produced the
desired indazoles with excellent yields (75–87%). The presence of
R1 as the electron-withdrawing group could enhance the electro-
philicity toward the N–O bond of the oximephosphonium ion inter-
mediate and facilitate the nucleophilic attack of the arylamino
group. This hypothesis was further supported by the excellent yield
of compound 2h (Table 2, entry 8), where R is electron-donating,
and R1 is the electron-withdrawing functional group.
copy (Fig.
1 and Fig. S1). The spectra were collected after
32.1
32.0
Ph
Ph P O
Ph
Ph
Ph
Ph P O
Ph
Ph
I
P
N O
NH2
Ph
Ph
41.1
40.8
Ph
I
N
P
Ph
N
Ph
We also tested secondary aniline oxime derivatives using the
optimized reaction conditions. N-methylaniline oxime resulted in
the corresponding 1H-indazole with moderate yield; however,
other secondary aniline oximes produced the desired 1H-indazole
with lower/no yield. This could be due to the bulkiness and nucle-
ophilicity of the secondary aniline toward the formation of substi-
tuted 1H-indazoles (Table 3). We also determine the scope of this
methodology for the intermolecular N–N bond formation by
20
0
40
60
Figure 1. Monitoring the progress of reaction by 31P NMR of o-amino benzophe-
none oxime in CDCl3.

S. Paul et al. / Tetrahedron Letters 55 (2014) 2480–2483
2483
addition of each reagent with a sufficient time gap. The observed
changes in their chemical shifts (Table S1) indicate the formation
of intermediate II and III. The downfield shift of the 31P NMR signal
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2014.03.001.
(D
d = 0.22 ppm) after addition of oxime to the intermediate II indi-
References and notes
cates the formation of intermediate III. Although the chemical shift
is very little, still in situ generation of triphenylphosphine oxide in
the reaction media indicates the formation of intermediate III.
In conclusion, we report a mild reaction method for the synthe-
sis of 1H-indazole derivatives in the presence of triphenylphos-
phine, I2, and imidazole. In particular, we have demonstrated the
formation of oximephosphonium ion intermediate during the for-
mation of inter- and intramolecular N–N bond. We have also
shown that the nucleophilicity of the arylamino group and electro-
philicity toward the N–O bond of oxime play an important role in
the synthesis of 1H-indazole derivatives. We believe this facile and
efficient method will serve as a useful alternative to the existing
methods for the synthesis of substituted 1H-indazoles.
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The authors are thankful to the DST (SB/FT/CS-131/2012), Govt.
of India, for financial support. We are thankful to CIF for instru-
mental support. Special thanks are due to Mr. Dipjyoti Talukdar
for technical support.
Supplementary data
Supplementary data (experimental section, characterization of
the unknown compounds, 31P NMR spectra) associated with this